TY  - CHAP
M1  - Book, Section
TI  - Lysosomal Acid Lipase Deficiency: The Continuous Spectra of Disease Variants
A1  - Grabowski, Gregory A.
A1  - Valayannopoulos, Vassili
A1  - Goodman, Zachary D.
A1  - Balwani, Manisha
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
PY  - 2019
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - Deficient  activity  of  lysosomal  acid  lipase  (LAL)  leads  to  the  accumulation  of  cholesteryl  esters  and  triglycerides  in  most  tissue.  These  substrates  of  LAL  highlight  the  central  role  of  this  enzyme  in  the  modulation  of  the  metabolisms  of  cholesterol  and  triglyceride  throughout  the  body.  Deficiency  of  LAL  (LALD)  leads  to  a  continuum  of  diseases  historically  divided  into  infantile-onset  LALD  (Wolman  disease)  and  childhood/adult-onset  LALD  (cholesteryl  ester  storage  disease).Infantile-onset  LALD  presents  in  the  first  month  postpartum  with  a  rapidly  progressive  course  leading  to  death  before  1  year  of  age.  Hepatosplenomegaly,  steatorrhea,  abdominal  distention,  severe  malabsorption  and  resultant  malnutrition,  and  adrenal  enlargement  with  or  without  calcification  are  evident  within  the  first  months  postpartum.Childhood/adult-onset  LALD  has  a  less  severe  clinical  course  that  is  highly  variable.  The  majority  of  patients  present  in  the  pediatric  age  group  with  significantly  progressive  disease.  There  has  been  a  paucity  of  patients  identified  in  the  third  to  fourth  decades.  Isolated  hepatomegaly  and  hypercholesterolemia  2b  or  mixed  dyslipidemia  patterns  can  be  the  presenting  signs.  Hepatic  fibrosis  with  progression  to  bridging  fibrosis  and  frank  cirrhosis  occurs.  Premature  atherosclerosis  may  occur.  Malabsorption  and  adrenal  calcifications  are  infrequent  to  rare.Infantile-onset  LALD  and  childhood/adult-onset  LALD  are  suspected  by  the  clinical  presentation,  and  the  diagnoses  are  confirmed  by  finding  LALD  in  cultured  skin  fibroblasts,  lymphocytes,  other  tissues,  or  dried  blood  spot  assays.  Prenatal  diagnosis  is  feasible  using  amniocytes  or  chorionic  villus  samples  for  enzyme  assay  or  molecular  analyses  in  genetically  characterized  families.Infantile-onset  and  childhood/adult-onset  LALD  are  autosomal  recessive  diseases,  caused  by  mutations  in  LIPA  that  maps  to  chromosome  10q23.2–q23.3  and  encodes  LAL.  Many  mutations  of  LIPA  have  been  found  in  infantile-onset  LALD  patients,  and  these  lead  to  severe  deficiency  or  absence  of  LAL  activity.  In  comparison,  the  many  mutations  of  LIPA  in  childhood/adult-onset  LALD  allow  the  expression  of  significant  residual  LAL  activity.  A  splice  junction  mutant  allele,  E8SJM-1  (c.894G>A),  that  is  common  in  the  Western  World  allows  the  expression  of  3–8%  of  wild-type  LAL  activity  and  the  apparent  attenuation  of  the  extreme  manifestations  of  infantile-onset  LALD.Therapies  have  included  hematopoietic  stem  cell  transplantation  in  infantile-onset  LALD,  but  the  outcomes  have  been  highly  variable,  with  very  high  mortality  and  morbidity  rates.  In  childhood/adult-onset  LALD,  use  of  3-hydroxy-3-methylglutaryl  coenzyme  A  reductase  inhibitors  to  suppress  cholesterol  and  apolipoprotein  B  production  has  been  successful  in  treating  the  hyperlipidemia  of  childhood/adult-onset  LALD,  but  these  have  little  if  any  effect  on  the  progressive  hepatic  disease.Specific  enzyme  therapy  with  human  recombinant  LAL  has  been  approved  by  the  European  Medicines  Agency  (EMA),  the  U.S.  Food  and  Drug  Administration  (FDA)  and  the  Japan  Ministry  of  Health,  Labour  and  Welfare  (MHLW)  for  amelioration  and  treatment  of  infantile-onset  and  childhood/adult  LALD.  
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/20
UR  - ommbid.mhmedical.com/content.aspx?aid=1181464537
ER  -